Dual Immune Check Point Blockade in MGMT-Unmethylated Newly Diagnosed Glioblastoma: NRG Oncology BN007, a Randomized Phase II/III Clinical Trial

Evaluation of Different Score Index for Predicting Prognosis in Gamma Knife Radiosurgical Treatment for Brain Metastasis

Evolving consolidation patterns and outcomes for a large cohort of patients with primary CNS lymphoma

The authors investigated whether stereotactic radiosurgery (SRS) alone improved outcomes for patients in recursive partitioning analysis (RPA) Classes 1 and 2 who had 1 to 3 brain metastases compared with whole-brain radiotherapy (WBRT). Data regarding 186 patients in RPA Classes 1 and 2 who had 1 to 3 brain metastases and who received either 30 to 40 grays (Gy) of WBRT (n = 91 patients) or 18 to 25 Gy SRS (n = 95 patients) were analyzed retrospectively. Eight other potential prognostic factors were evaluated regarding overall survival (OS), entire brain control (BC), local control (LC) of treated metastases, and brain control distant from treated metastases (distant control [DC]): Those 8 factors were age, sex, performance status, tumor type, number of brain metastases, extracranial metastases, RPA class, and interval from tumor diagnosis to radiotherapy. On multivariate analysis of OS, age ( risk ratio [RR], 1.51; P = .024), Karnofsky performance status (KPS) (RR, 1.98; P = .002), and extracranial metastases (RR, 2.26; P < .001) were significant, whereas the radiation regimen was not significant (P = .89). On multivariate analysis of BC, only the radiation regimen (RR, 1.33; P = .003) was found to be significant. On multivariate analysis of LC, radiation regimen (RR, 1.63; P < .001) and sex (RR, 1.62; P = .022) were significant. On multivariate analysis of DC, KPS (RR, 1.85; P = .049) and extracranial metastases (RR, 1.69; P = .047) were significant. The radiation regimen was not found to be significant even on univariate analysis (P = .80). In RPA class subgroup analyses, BC and LC were better after SRS than WBRT for patients in RPA Classes 1 and 2, whereas OS and DC did not differ significantly. For patients in RPA Classes 1 and 2 who had 1 to 3 brain metastases, SRS alone was associated with improved BC and LC compared with 30 to 40 Gy WBRT, whereas OS and DC were not significantly different. Similar results were observed in separate subgroup analyses of patients in RPA Class 1 and RPA Class 2.

The purpose of this study was to evaluate prognostic factors associated with overall survival (OS) and neurological progression free survival (nPFS) in small-cell lung cancer (SCLC) patients with brain metastases who received whole-brain radiotherapy (WBRT). From 2003 to 2015, 229 SCLC patients diagnosed with brain metastases who received WBRT were analyzed retrospectively. In this cohort 219 patients (95%) received a total photon dose of 30Gy in 10 fractions. The prognostic factors evaluated for OS and nPFS were: age, Karnofsky Performance Status (KPS), number of brain metastases, synchronous versus metachronous disease, initial response to chemotherapy, the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) class and thoracic radiation. Median OS after WBRT was 6months and the median nPFS after WBRT was 11months. Patients with synchronous cerebral metastases had a significantly better median OS with 8months compared to patients with metachronous metastases with a median survival of 3months (p < 0.0001; HR 0.46; 95% CI 0.31-0.67). Based on RPA classification median survival after WBRT was 17months in RPA class I, 7months in class II and 3months in class III (p < 0.0001). Karnofsky performance status scale (KPS < 70%) was significantly associated with OS in both univariate (HR 2.84; p < 0.001) and multivariate analyses (HR 2.56; p = 0.011). Further, metachronous brain metastases (HR 1.8; p < 0.001), initial response to first-line chemotherapy (HR 0.51, p < 0.001) and RPA class III (HR 2.74; p < 0.001) were significantly associated with OS in univariate analysis. In multivariate analysis metachronous disease (HR 1.89; p < 0.001) and initial response to chemotherapy (HR 0.61; p < 0.001) were further identified as significant prognostic factors. NPFS was negatively significantly influenced by poor KPS (HR 2.56; p = 0.011), higher number of brain metastases (HR 1.97; p = 0.02), and higher RPA class (HR 2.26; p = 0.03) in univariate analysis. In this series, the main prognostic factors associated with OS were performance status, time of appearance of intracranial disease (synchronous vs. metachronous), initial response to chemotherapy and higher RPA class. NPFS was negatively influenced by poor KPS, multiplicity of brain metastases, and higher RPA class in univariate analysis. For patients with low performance status, metachronous disease or RPA class III, WBRT should be weighed against supportive therapy with steroids alone or palliative chemotherapy.

The objective of this study was to compare stereotactic radiosurgery (SRS) alone with resection plus whole-brain radiotherapy (WBRT) for the treatment of patients in recursive partitioning analysis (RPA) class 1 and 2 who had 1 or 2 brain metastases. Two hundred six patients in RPA class 1 and 2 who had 1 or 2 brain metastases were analyzed retrospectively. Patients in Group A (n = 94) received from 18 grays (Gy) to 25 Gy SRS, and patients in Group B (n = 112) underwent resection of their metastases and received 10 x 3 Gy/20 x 2 Gy WBRT. Eight other potential prognostic factors were evaluated regarding overall survival (OS), brain control (BC), and local control (LC) of treated metastases: age, sex, performance status, tumor type, number of brain metastases, extracranial metastases, RPA class, and interval from tumor diagnosis to treatment of brain metastases. A comparison of the 2 treatment groups did not reveal significantly different OS (P = .19), BC (P = .52), or LC (P = .25). In RPA subgroup analyses, outcome also did not differ significantly for either RPA class of patients (P values from .21 to .83). On multivariate analysis, improved OS was associated with age < or =60 years (relative risk [RR], 1.75; P = .002), better performance status (RR, 1.67; P = .015), no extracranial metastases (RR, 2.84; P < .001), interval from tumor diagnosis to treatment >12 months (RR, 1.70; P = .003), and RPA class 1 (RR, 1.51; P = .016). Improved BC was associated with a single metastasis (RR, 1.54; P = .034) and an interval from tumor diagnosis to treatment >12 months (RR, 1.58; P = .019), and improved LC was associated with an interval from tumor diagnosis to treatment >12 months (RR, 1.59; P = .047). SRS alone appeared to be as effective as resection plus WBRT in the treatment of 1 or 2 brain metastases for patients in RPA class 1 and 2. Patient outcomes were associated with age, Karnofsky performance status, number of brain metastases, extracranial metastases, RPA class, and interval from tumor diagnosis to treatment.

Prognostic factors in brain metastases: should patients be selected for aggressive treatment according to recursive partitioning analysis (RPA) classes?

The current study was conducted to compare 2 treatment regimens including surgical resection and whole-brain radiotherapy (WBRT) for patients with 1 to 2 brain metastases. A total of 201 patients with recursive partitioning analysis (RPA) class 1 to 2 disease with 1 to 2 resectable brain metastases were analyzed retrospectively. Patients underwent either resection of the metastases plus WBRT with 10 fractions of 3 grays (Gy) each or 20 fractions of 2 Gy each (99 patients; Group A) or the same treatment plus a WBRT boost to the metastatic site (10 fractions of 3 Gy each plus 5 fractions of 3 Gy each or 20 fractions of 2 Gy each plus 5 fractions of 2 Gy each) (102 patients; Group B). Eight other potential prognostic factors were evaluated with regard to overall survival (OS), brain control (BC), and local control of resected metastases (LC): age, gender, Karnofsky performance status, extent of surgical resection, tumor type, extracranial metastases, RPA class, and interval from tumor diagnosis to WBRT. Group B patients had better 1-year OS (66% vs 41%; P < .001). On multivariate analysis of OS, treatment regimen (relative risk [RR] of 1.94; P < .001), extent of surgical resection (RR of 1.80; P = .001), and interval from tumor diagnosis to WBRT (RR of 1.62; P = .010) were found to be statistically significant. On multivariate analysis of BC, treatment regimen (RR of 2.15; P = .002), extent of surgical resection (RR of 2.78; P < .001), and interval from tumor diagnosis to WBRT (RR of 1.52; P = .034) were found to be statistically significant. On multivariate analysis of LC, treatment regimen (RR of 2.31; P = .002) and extent of surgical resection (RR of 3.79; P < .001) were found to be statistically significant. On RPA class subgroup analyses, outcome was found to be significantly better with a WBRT boost in both RPA class 1 and class 2 patients. A WBRT boost resulted in better outcome after both complete and incomplete surgical resection. However, the results concerning BC and LC were not found to be statistically significant if surgical resection was incomplete. After surgical resection of 1 to 2 brain metastases, a boost of 10 to 15 Gy in addition to WBRT was found to improve outcome. After incomplete surgical resection, further dose escalation to the metastatic site may be considered.

Multi-Institutional Datasets Validate the Recursive Partitioning Analysis for Overall Survival in Patients Undergoing Spine Radiosurgery for Spine Metastasis

OBJECTIVE The purpose of the present study was to investigate the epigenetic and prognostic roles of an H3K4 methyltransferase (mixed lineage leukemia 4 [MLL4]) and H3K27 demethylase (ubiquitously transcribed tetratricopeptide repeat gene on X chromosome [UTX]) in progression-free survival (PFS) and overall survival (OS) of patients with glioblastoma (GBM) who were treated with radiotherapy, chemotherapy, or both after resection. In addition, the authors examined methylation at the promoter of the O-6-methylguanine-DNA methyltransferase ( MGMT) gene and other prognostic factors predicting length of PFS and OS in these patients. METHODS The medical records of 76 patients having a new diagnosis of histologically ascertained GBM in the period of January 2002 to December 2013 at the authors' institution were retrospectively reviewed. Immunohistochemical staining for MLL4 and UTX was performed on archived paraffin-embedded tissues obtained by biopsy or resection. The methylation status of the MGMT promoter in these tissues was determined by methylation-specific PCR analysis. RESULTS During the follow-up period (mean length 18.1 months, range 4.1-43.5 months), 68 (89.5%) of the patients died. The MGMT promoter was methylated in 49 patients (64.5%) and unmethylated in 27 (35.5%). The immunoreactivity pattern of UTX was identical to that of MLL4; increased expression of these 2 proteins was observed in samples from 34 patients (44.7%) and decreased expression in 42 patients (55.3%). The mean length of PFS was 9.2 months (95% CI 6.8-11.6 months). Extent of surgery, recursive partitioning analysis (RPA) class, and methylation status of the MGMT promoter were all associated with increased PFS in the multivariate analysis of factors predicting PFS. The mean length of OS was 18.6 months (95% CI 14.3-22.9 months). Patient age (p = 0.004), WHO performance status score (p = 0.019), extent of surgery (p = 0.007), RPA class (p = 0.036), methylation status of the MGMT promoter (p = 0.010), and increased expression of UTX-MLL4 (p = 0.001) were significantly associated with increased OS in multivariate analysis. Interestingly, in patients with an unmethylated MGMT promoter, immunoreactivity of UTX-MLL4 was not associated with changes in OS (p = 0.350). However, in the patients with a methylated MGMT promoter, increased UTX-MLL4 expression was strongly associated with increased OS (p < 0.001). CONCLUSIONS The results of this study suggest that increased expression of UTX-MLL4 positively influences the outcome of patients with GBM having a methylated MGMT promoter. Therefore, UTX-MLL4 immunoreactivity could be a useful predictor of the response to conventional treatment with radiotherapy or chemotherapy among GBM patients whose tumors have a methylated MGMT promoter.

Objectives : Lung cancer is one of the leading causes of cancer deaths in India. Fifteen to 35% of patients present with Brain Metastasis (BM) and are treated with palliative Whole Brain Radiotherapy (WBRT). We report the survival outcomes and prognostic factors of lung cancer patients with BM. Methods: Two hundred and twenty-one patients were analysed from July 2010 - June 2014 who received palliative WBRT. Overall Survival (OS) was computed using Kaplan Meier method. Difference in survival for known prognostic factors were analysed using log rank test with significance of p value at 0.05 and 95% confidence interval. Results: Median OS was 3.7 months. OS at 6, 12 and 24 months was 36%, 24% and 13.8% respectively. Synchronous BM patients had significantly better OS compared to those with metachronous BM with a hazard ratio (HR) 0.62 (95% CI 0.46-0.85, p=0.01). Patients with a higher Graded Prognostic Assessment (GPA) score, a Recursive Partitioning Analysis (RPA) class of I-II and adenocarcinoma histology had comparatively better OS. There was a subset of patients (n=58) who died within 30 days of diagnosis of BM. Neither RPA class nor GPA score could accurately predict patients who were within the 30 day mortality group. Conclusion: Patients of lung cancer with BM have poor outcome. GPA score of 3.5-4.0, RPA class I-II and adenocarcinoma histology showed better survival outcomes. However, neither GPA nor RPA could predict 30 day mortality.

Multi-Institutional Validation of the Recursive Partitioning Analysis for Overall Survival in Patients Undergoing Spine Radiosurgery for Spine Metastasis

Stereotactic radiosurgery (SRS) is considered the initial treatment for lung cancer patients with small-sized and limited number of brain metastases. The objective of this study was to assess clinical outcomes of SRS treatment using CyberKnife (CK) for recursive partitioning analysis (RPA) class II/III patients with 1 to 3 brain metastases from lung cancer and identify which patients in the high RPA class could benefit from SRS.A total of 48 lung cancer patients who received CK-based SRS for their metastatic brain lesions from 2010 to 2017 were retrospectively analyzed. Radiographic response was evaluated during follow-up period. Overall survival (OS) and intracranial progression-free survival (IPFS) were calculated and prognostic variables associated with OS and IPFS were evaluated.Median follow-up time was 6.6 months. Local control rates at 6 months and 1-year following SRS were 98% and 92%, respectively. The median OS of all patients was 8 months. One-year and 2-year OS rates were 40.8% and 20.9%, respectively. In multivariate analysis, uncontrolled primary disease (P = .01) and Eastern Cooperative Oncology Group performance status of 2 or 3 (P = .001) were independent prognostic factors for inferior OS. These 2 factors were also significantly associated with inferior IPFS. In subgroup analysis according to RPA class, primary disease status was the only prognostic factor, showing statistically significant OS differences in both RPA class II and III (controlled vs uncontrolled: 41.1 vs 12.3 months in RPA class II, P = .03; 26.9 vs 4.1 months in RPA class III, P = .01).Our results indicated that SRS could be an effective treatment option for RPA class II/III patients with brain metastases from lung cancer in the modern treatment era. SRS might be particularly considered for patients with controlled primary disease.

BackgroundThe aim of this study was to survey prognostic factors, particularly those focusing on epidermal growth factor receptor (EGFR) mutations, of patients with non-small cell lung cancer (NSCLC) after Gamma Knife Radiosurgery (GKRS) for metastatic brain tumors.MethodsWe retrospectively reviewed the medical records of 98 patients with NSCLC who underwent GKRS for brain metastases from August 2010 to July 2017. The primary endpoint was progression-free survival (PFS) of the intracranial disease. We analyzed variables such as age, sex, Karnofsky Performance Status, recursive partitioning analysis (RPA) class, smoking status, primary cancer pathology, EGFR mutations, and time to brain metastases as prognostic factors.ResultsThe median overall survival (OS) of the patients was 16 months [95% confidence interval (CI), 13–21 months]. Median systemic PFS and intracranial PFS were 9 months (95% CI, 8–11 months) and 11 months (95% CI, 7–14 months), respectively. Kaplan-Meier survival analysis revealed that the patients with EGFR mutations had longer intracranial PFS than those without EGFR mutation (median intracranial PFS: 19 vs. 10 months with p=0.01) while they had no benefits in OS and systemic PFS. Furthermore, the patients harboring adenocarcinoma had longer OS (p<0.01) and intracranial PFS (p<0.01) and the patients with lower RPA class had longer OS (p=0.02) and intracranial PFS (p=0.03).ConclusionEGFR mutations, primary cancer pathology, and RPA class may be proposed as prognostic factors for intracranial PFS in NSCLC patients after GKRS for brain metastasis in this study.

Quantitative measurement of regional signal intensity changes of high grade gliomas following radiotherapy using T1-weighted contrast enhanced MRI imaging

Validation and Predictive Power of Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis Classes for Malignant Glioma Patients: A Report Using RTOG 90-06